Acute pain and chronic pain are significant complications in many human diseases, prime examples being cancer, diabetic disorders, and traumatic injury. In preliminary studies, my colleagues and I used high throughput in situ hybridization to develop a genome-scale expression map of transcription factors in developing mouse embryos. We then used this map, in combination with targeted gene disruption methods, to identify key proteins for specification of nociceptive/pain sensory neurons (nociceptors). This work led to identification of the transcription factor Runxl as a pivotal agent in development of nociceptors for thermal and neuropathic pain. The research described here builds upon this preliminary work. The goal of our research over the next five years is to define the molecular mechanisms that allow a single transcription factor (Runxl) to control the formation of a large cohort of nociceptors and the assembly of specific neural circuits for the perception of pain. We have four specific Aims. Aim 1 is to determine how Runxl expression controls the segregation of two major nociceptor subtypes, non-peptidergic versus peptidergic. Aim 2 is to address how Runxl regulates the expression of nociceptive ion channels and receptors, with the goal of understanding the logic underlying the generation of tremendous diversity within the non-peptidergic population of nociceptors. Aim 3 focuses on the assembly of pain circuits. Here we want to determine how Runxl controls the innovation of non-peptidergic nociceptors to specific peripheral and central targets. Aim 4 is to determine how distinct Runxl-dependent programs contribute to behavioral response to noxious stimuli. For each of these four aims, we have preliminary data that leads to a testable hypothesis. The predictions of these hypotheses will be tested by using a panel of genetic tools that we have already developed. In the fullness of time, the work may lead to a novel biological target and therapeutic approach for pain management.